The present invention relates to the oxofuryl ester derivatives of 6-(.alpha.-aminophenylacetamido)penicillanic acid, 7-(.alpha.-aminophenylacetamido)cephalosporanic acid, or 7-(.alpha.-aminophenylacetamido)desacetoxycephalosporanic acid represented by the general formula ##SPC3##
Wherein A represents ##SPC4##
Wherein R.sup.1 and R.sup.2, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, said R.sup.1 and R.sup.2 may form together a 1,3-butadienylene group, R.sup.3 represents a hydrogen atom or an acetoxy group, and ,
Means a single bond or a double bond, and the acid addition salts thereof.
When the compounds of this invention are orally administered, they are readily absorbed by intestines and show antibacterial activity by splitting the ester bonds in the body.
Although 6-(.alpha.-aminophenylacetamido)penicillanic acid (hereinafter, the acid is called "ampicillin") is well known as a semi-synthetic penicillin that can be orally administered, the extent of the absorption by oral administration is not necessarily sufficient and thus it has been desired to increase the amount of ampicillin to be absorbed by oral administration. As ampicillin derivatives fulfil the above desire, the acyloxymethyl ester of ampicillin, in particular, the pivaloyloxymethyl ester of ampicillin (hereinafter, the ester is called "pivampicillin) has been developed (Belgian Pat. No. 721,525 and Jour. Med. Chem., 13, 607-612(1970)).
Also, the acyloxymethyl esters of 7-(.alpha.-aminophenylacetamido)cephalosporanic acid (hereinafter, the acid is called "cephaloglycin") and 7-(.alpha.-aminophenylacetamido)desacetoxycephalosporanic acid (hereinafter, the acid is called "cephalexin") have been developed as the readily absorbable derivatives of the acids (German Offenlegungsschriften Nos. 1,904,585 and 1,951,012).
It has been said that each of the acyloxymethyl esters as mentioned above be absorbed in the intestines and hydrolyzed enzymatically to isolate formaldehyde and the acid and to show antibacterial acitivity as ampicillin, cephaloglycin or cephalexin. Thus, the problem of increasing the absorption of ampicillin, cephaloglycin, or cephalexin by oral administration may be once at least solved by the discovery of the acyloxymethyl esters of them but those acyloxymethyl esters have not yet been practically used as medicaments since the presence of hepatotoxicity has unfortunately been found in the step of the toxicological evaluation (Antimicrobial Agents and Chemotherapy -- 1970, pages 442-454, in particular, page 453). There are no descriptions about the cause of the hepatotoxicity in the above literature but it has hitherto been known that formaldehyde shows high toxic property (about 50 times) as compared with those of other aldehydes having molecular weights larger than that of formaldehyde (Chemical Abstracts, 45, 4824h (1951) and ibid., 55, 8653d (1961) ) and also it gives bad influences on a liver (Biochem. Pharmacol., 16, 1533-1537 (1967); Chemical Abstracts, 69, 58092x (1968); and Biochem. Jour., 111, 665-678 (1969) ). Upon considering those facts, the inventors have noticed that the cause of the hepatotoxicity is based on the formaldehyde liberated from the acyloxymethyl ester in the body and have discovered as the results of the investigations of the readily absorbable derivatives of cephaloglycin or cephalexin which will not liberate formaldehyde in the body that the novel oxofuryl ester compounds represented by the aforesaid general formula V are readily absorbed in the intestines when they are orally administered and converted into ampicillin, cephaloglycin or cephalexin by splitting enzymatically their ester bonds in blood to show antibacterial activity.
It has never been anticipated from the prior arts that the oxofuryl esters show good absorbable property in intestines by oral administration and give a high concentration thereof in blood in spite of the great different structures thereof from those of the known acyloxymethyl esters.
It will be clear from the chemical structure of the compound that the oxofuryl ester of this invention does not release formaldehyde or similar aldehydes in the body, which is one of the features of this invention. Moreover, the compounds of this invention are stable to .beta.-lactamase, which is other feature of this invention.
Thus, the problem of obtaining the derivatives of penicillin and cephalosporin having no toxicity and showing good absorbable property in intestines by oral administration has been solved by the present invention.